Process for producing a plasma protein-containing medicament with reduced concentration of citrate and metals

Abstract

There is disclosed a method of preparing a plasma-protein-containing medicament from citrated plasma or from a citrate-containing plasma fraction, the medicament being substantially free from undesired metals, which method comprises the following steps: exchanging the citrate and optionally citrate-bound metals in a plasma-protein-containing solution for a water-soluble mono- or dicarboxylate or for an organic mono- or dicarboxylic acid under non-precipitating conditions, recovering the plasma protein or the plasma proteins, and finishing the medicament.

The invention claimed is: 
     
       1. A method of preparing a plasma-protein-containing medicament from citrated plasma or from a citrate-containing plasma fraction, wherein the medicament has a reduced concentration of undesired metals selected from the group consisting of aluminum, cadmium, zinc, lead and iron, wherein the method comprises the steps of:
 (a) obtaining citrated plasma or citrate-containing plasma fraction by Cohn fractionation; 
 (b) adding to the citrated plasma or citrate-containing plasma fraction, a compound to achieve a solution having the compound concentration of between 0.001 and 1.00 mol/liter, wherein the compound is selected from the group consisting of a monocarboxylate, a dicarboxylate, a monocarboxylic acid and a dicarboxylic acid; 
 (c) exchanging the citrate and citrate-bound metals that may be present in the plasma or plasma fraction with the compound by diafiltration, ultrafiltration or chromatography at a temperature above 0° C. to 50° C. and at a pH of 6 to 8, under non-precipitating conditions, thereby reducing the concentration of citrate and the undesired metals that may have been present; 
 (d) recovering one or more plasma proteins; and 
 (e) finishing the medicament. 
 
     
     
       2. The method as set forth in  claim 1 , wherein the compound has 2 to 20 carbon atoms. 
     
     
       3. The method as set forth in  claim 1 , wherein the compound is selected from the group consisting of caprylate, tartrate, hexanoic acid and acetate. 
     
     
       4. The method as set forth in  claim 1 , further comprising subjecting the citrated plasma or a citrate-containing plasma fraction to a purification procedure before the reducing. 
     
     
       5. The method as set forth in  claim 1 , further comprising subjecting the citrated plasma or a citrate-containing plasma fraction to a concentration procedure before the reducing. 
     
     
       6. The method as set forth in  claim 1 , further comprising subjecting the citrated plasma or a citrate-containing plasma fraction to a treatment for virus inactivation. 
     
     
       7. The method as set forth in  claim 6 , wherein the treatment for virus inactivation is performed before the exchanging. 
     
     
       8. The method as set forth in  claim 6 , wherein the treatment for virus inactivation is performed after the exchanging. 
     
     
       9. The method as set forth in  claim 6 , wherein the treatment for virus inactivation is performed both before and after the exchanging. 
     
     
       10. The method as set forth in  claim 6 , wherein the treatment for virus-inactivation is a heat-treatment. 
     
     
       11. The method as set forth in  claim 6 , wherein the treatment for virus inactivation is performed immediately after the recovering of at least one plasma protein. 
     
     
       12. The method as set forth in  claim 1 , wherein the finishing of the medicament is performed using only citrate-free components. 
     
     
       13. The method according to  claim 1 , wherein the exchanging occurs at a pH of 6.5 to 7.5. 
     
     
       14. The method according to  claim 1 , wherein the exchanging occurs at a temperature of 10° C. to 30° C. 
     
     
       15. The method according to  claim 1 , wherein the exchanging occurs at room temperature. 
     
     
       16. The method according to  claim 1 , wherein the plasma proteins for the medicament are selected from the group consisting of albumin, coagulation factors, fibrinolysis factors, immunoglobulins and glycoproteins. 
     
     
       17. A method of preparing a plasma-protein-containing medicament from a Cohn fraction comprising plasma proteins and citrate, wherein the medicament has a reduced concentration of undesired metals selected from the group consisting of aluminum, cadmium, zinc, lead and iron, wherein the method comprises the steps of:
 (a) adding to the Cohn fraction a compound to achieve a solution having the compound concentration of between 0.001 and 1.00 mol/liter, wherein the compound is selected from the group consisting of a monocarboxylate, a dicarboxylate, a monocarboxylic acid and a dicarboxylic acid; 
 (b) exchanging the citrate and citrate-bound metals that may be present in the Cohn fraction with the compound by diafiltration, ultrafiltration or chromatography at a temperature above 0° C. to 50° C. and at a pH of 6 to 8, under non-precipitating conditions, thereby reducing the concentration of citrate and the undesired metals that may have been present; 
 (c) recovering one or more plasma proteins; and 
 (d) finishing the medicament. 
 
     
     
       18. The method as set forth in  claim 17 , wherein the compound has 2 to 20 carbon atoms. 
     
     
       19. The method as set forth in  claim 17 , wherein the compound is selected from the group consisting of caprylate, tartrate, hexanoic acid and acetate. 
     
     
       20. The method as set forth in  claim 17 , further comprising subjecting the plasma-protein-containing solution to a purification procedure before the exchanging. 
     
     
       21. The method as set forth in  claim 17 , further comprising subjecting the plasma-protein-containing solution to a concentration procedure before the exchanging. 
     
     
       22. The method as set forth in  claim 17 , further comprising subjecting the medicament to a treatment for virus inactivation. 
     
     
       23. The method as set forth in  claim 22 , wherein the treatment for virus inactivation is performed before the exchanging. 
     
     
       24. The method as set forth in  claim 22 , wherein the treatment for virus inactivation is performed after the exchanging. 
     
     
       25. The method as set forth in  claim 22 , wherein the treatment for virus inactivation is performed both before and after the exchanging. 
     
     
       26. The method as set forth in  claim 22 , wherein the treatment for virus-inactivation is a heat-treatment. 
     
     
       27. The method as set forth in  claim 22 , wherein the treatment for virus inactivation is performed immediately after the recovering of at least one plasma protein. 
     
     
       28. The method as set forth in  claim 17 , wherein the finishing of the medicament is performed using only citrate-free components. 
     
     
       29. The method according to  claim 17 , wherein the exchanging occurs at a pH of 6.5 to 7.5. 
     
     
       30. The method according to  claim 17 , wherein the exchanging occurs at a temperature of 10° C. to 30° C. 
     
     
       31. The method according to  claim 17 , wherein the exchanging occurs at room temperature. 
     
     
       32. The method according to  claim 17 , wherein the plasma proteins for the medicament are selected from the group consisting of albumin, coagulation factors, fibrinolysis factors, immunoglobulins and glycoproteins.